The tumor suppressor LKB1 is an essential serine/threonine kinase, which regulates various cellular processes such as cell metabolism, cell proliferation, cell polarity, and cell migration. Germline mutations in the STK11 gene (encoding LKB1) are the cause of the Peutz-Jeghers syndrome, which is characterized by benign polyps in the intestine and a higher risk for the patients to develop intestinal and extraintestinal tumors. Moreover, mutations and misregulation of LKB1 have been reported to occur in most types of tumors and are among the most common aberrations in lung cancer. LKB1 activates several downstream kinases of the AMPK family by direct phosphorylation in the T-loop. In particular the activation of AMPK upon energetic stress has been intensively analyzed in various diseases, including cancer to induce a metabolic switch from anabolism towards catabolism to regulate energy homeostasis and cell survival. In contrast, the regulation of LKB1 itself has long been only poorly understood. Only in the last years, several proteins and posttranslational modifications of LKB1 have been analyzed to control its localization, activity and recognition of substrates. Here, we summarize the current knowledge about the upstream regulation of LKB1, which is important for the understanding of the pathogenesis of many types of tumors.
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Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 1998;391:184–7.
Jansen M, Klooster JPten, Offerhaus GJ, Clevers H. LKB1 and AMPK family signaling. Intim Link Cell polarity Energy Metab Physiol Rev. 2009;89:777–98.
Mehenni H, Gehrig C, Nezu J, Oku A, Shimane M, Rossier C, et al. Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am J Hum Genet. 1998;63:1641–50.
Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman LA, Gille JJP, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 2006;12:3209–15.
Miyoshi H, Nakau M, Ishikawa T-o, Seldin MF, Oshima M, Taketo MM. Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res. 2002;62:2261–6.
Bardeesy N, Sinha M, Hezel AF, Signoretti S, Hathaway NA, Sharpless NE, et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature. 2002;419:162–7.
Jishage K-i, Nezu J-i, Kawase Y, Iwata T, Watanabe M, Miyoshi A, et al. Role of Lkb1, the causative gene of Peutz-Jegher’s syndrome, in embryogenesis and polyposis. Proc Natl Acad Sci USA. 2002;99:8903–8.
Rossi DJ, Ylikorkala A, Korsisaari N, Salovaara R, Luukko K, Launonen V, et al. Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis. Proc Natl Acad Sci USA. 2002;99:12327–32.
Wei C, Amos CI, Stephens LC, Campos I, Deng JM, Behringer RR, et al. Mutation of Lkb1 and p53 genes exert a cooperative effect on tumorigenesis. Cancer Res. 2005;65:11297–303.
McGarrity TJ, Kulin HE, Zaino RJ. Peutz-Jeghers syndrome. Am J Gastroenterol. 2000;95:596–604.
Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM, et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 2002;62:3659–62.
Matsumoto S, Iwakawa R, Takahashi K, Kohno T, Nakanishi Y, Matsuno Y, et al. Prevalence and specificity of LKB1 genetic alterations in lung cancers. Oncogene. 2007;26:5911–8.
Gill RK, Yang S-H, Meerzaman D, Mechanic LE, Bowman ED, Jeon H-S, et al. Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer. Oncogene. 2011;30:3784–91.
Carretero J, Medina PP, Pio R, Montuenga LM, Sanchez-Cespedes M. Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene. Oncogene. 2004;23:4037–40.
Wingo SN, Gallardo TD, Akbay EA, Liang M-C, Contreras CM, Boren T, et al. Somatic LKB1 mutations promote cervical cancer progression. PLoS ONE. 2009;4:e5137.
Tanwar PS, Mohapatra G, Chiang S, Engler DA, Zhang L, Kaneko-Tarui T, et al. Loss of LKB1 and PTEN tumor suppressor genes in the ovarian surface epithelium induces papillary serous ovarian cancer. Carcinogenesis. 2014;35:546–53.
George SHL, Milea A, Sowamber R, Chehade R, Tone A, Shaw PA. Loss of LKB1 and p53 synergizes to alter fallopian tube epithelial phenotype and high-grade serous tumorigenesis. Oncogene. 2015;35:59–68.
Morton JP, Jamieson NB, Karim SA, Athineos D, Ridgway RA, Nixon C, et al. LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest. Gastroenterology. 2010;139:586–97. 597.e1-6
Guldberg P, thor Straten P, Ahrenkiel V, Seremet T, Kirkin AF, Zeuthen J. Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma. Oncogene. 1999;18:1777–80.
Rowan A, Bataille V, MacKie R, Healy E, Bicknell D, Bodmer W, et al. Somatic mutations in the Peutz-Jeghers (LKB1/STKII) gene in sporadic malignant melanomas. J Invest Dermatol. 1999;112:509–11.
Dogliotti G, Kullmann L, Dhumale P, Thiele C, Panichkina O, Mendl G, et al. Membrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumour suppression. Nat Commun. 2017;8:15747.
Cidlinsky N, Dogliotti G, Pukrop T, Jung R, Weber F, Krahn MP. Inactivation of the LKB1-AMPK signaling pathway does not contribute to salivary gland tumor development—a short report. Cell Oncol. 2016;39:389–96.
Sengupta S, Nagalingam A, Muniraj N, Bonner MY, Mistriotis P, Afthinos A, et al. Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3. Oncogene. 2017;36:5709–21.
Shen Z, Wen X-F, Lan F, Shen Z-Z, Shao Z-M. The tumor suppressor gene LKB1 is associated with prognosis in human breast carcinoma. Clin Cancer Res. 2002;8:2085–90.
Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LGD, Neumann D, et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol. 2003;13:2004–8.
Jaleel M, McBride A, Lizcano JM, Deak M, Toth R, Morrice NA, et al. Identification of the sucrose non-fermenting related kinase SNRK, as a novel LKB1 substrate. FEBS Lett. 2005;579:1417–23.
Lizcano JM, Göransson O, Toth R, Deak M, Morrice NA, Boudeau J, et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 2004;23:833–43.
Benton R, St Johnston D. Drosophila PAR-1 and 14–3–3 inhibit Bazooka/PAR-3 to establish complementary cortical domains in polarized cells. Cell. 2003;115:691–704.
Amin N, Khan A, St Johnston D, Tomlinson I, Martin S, Brenman J, et al. LKB1 regulates polarity remodeling and adherens junction formation in the Drosophila eye. Proc Natl Acad Sci USA. 2009;106:8941–6.
Granot Z, Swisa A, Magenheim J, Stolovich-Rain M, Fujimoto W, Manduchi E, et al. LKB1 regulates pancreatic beta cell size, polarity, and function. Cell Metab. 2009;10:296–308.
Lee JH, Koh H, Kim M, Kim Y, Lee SY, Karess RE, et al. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature. 2007;447:1017–20.
Bultot L, Horman S, Neumann D, Walsh MP, Hue L, Rider MH. Myosin light chains are not a physiological substrate of AMPK in the control of cell structure changes. FEBS Lett. 2009;583:25–28.
Barnes AP, Lilley BN, Pan YA, Plummer LJ, Powell AW, Raines AN, et al. LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons. Cell. 2007;129:549–63.
Courchet J, Lewis TL, Lee S, Courchet V, Liou D-Y, Aizawa S, et al. Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture. Cell. 2013;153:1510–25.
Dorfman J, Macara IG. STRADalpha regulates LKB1 localization by blocking access to importin-alpha, and by association with Crm1 and exportin-7. Mol Biol Cell. 2008;19:1614–26.
Smith DP, Spicer J, Smith A, Swift S, Ashworth A. The mouse Peutz-Jeghers syndrome gene Lkb1 encodes a nuclear protein kinase. Hum Mol Genet. 1999;8:1479–85.
Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA, et al. Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. EMBO J. 2003;22:3062–72.
Boudeau J, Baas AF, Deak M, Morrice NA, Kieloch A, Schutkowski M, et al. MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm. EMBO J. 2003;22:5102–14.
Nezu J, Oku A, Shimane M. Loss of cytoplasmic retention ability of mutant LKB1 found in Peutz-Jeghers syndrome patients. Biochem Biophys Res Commun. 1999;261:750–5.
Boudeau J, Scott JW, Resta N, Deak M, Kieloch A, Komander D, et al. Analysis of the LKB1-STRAD-MO25 complex. J Cell Sci. 2004;117:6365–75.
Zeqiraj E, Filippi BM, Deak M, Alessi DR, van Aalten DMF. Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. Science. 2009;326:1707–11.
Collins SP, Reoma JL, Gamm DM, Uhler MD. LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo. Biochem J. 2000;345:673–80.
Sapkota GP, Kieloch A, Lizcano JM, Lain S, Arthur JS, Williams MR, et al. Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 byp90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell vrowth. J Biol Chem. 2001;276:19469–82.
Sapkota GP, Deak M, Kieloch A, Morrice N, Goodarzi AA, Smythe C, et al. Ionizing radiation induces ataxia telangiectasia mutated kinase (ATM)-mediated phosphorylation of LKB1/STK11 at Thr-366. Biochem J. 2002;368:507–16.
Sapkota GP, Boudeau J, Deak M, Kieloch A, Morrice N, Alessi DR. Identification and characterization of four novel phosphorylation sites (Ser31, Ser325, Thr336 and Thr366) on LKB1/STK11, the protein kinase mutated in Peutz-Jeghers cancer syndrome. Biochem J. 2002;362:481–90.
Xie Z, Dong Y, Zhang M, Cui M-Z, Cohen RA, Riek U, et al. Activation of protein kinase C zeta by peroxynitrite regulates LKB1-dependent AMP-activated protein kinase in cultured endothelial cells. J Biol Chem. 2006;281:6366–75.
Bai Y, Zhou T, Fu H, Sun H, Huang B. 14-3-3 interacts with LKB1 via recognizing phosphorylated threonine 336 residue and suppresses LKB1 kinase function. FEBS Lett. 2012;586:1111–9.
Zhang Y-L, Guo H, Zhang C-S, Lin S-Y, Yin Z, Peng Y, et al. AMP as a low-energy charge signal autonomously initiates assembly of AXIN-AMPK-LKB1 complex for AMPK activation. Cell Metab. 2013;18:546–55.
Zhang C-S, Jiang B, Li M, Zhu M, Peng Y, Zhang Y-L, et al. The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab. 2014;20:526–40.
Chen J, Ou Y, Li Y, Hu S, Shao L-W, Liu Y. Metformin extends C. elegans lifespan through lysosomal pathway. Elife. 2017;6:e31268.
Zhang C-S, Hawley SA, Zong Y, Li M, Wang Z, Gray A, et al. Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature. 2017;548:112–6.
Tortelote GG, Reis RR, Almeida Mendes Fde, Abreu JG. Complexity of the Wnt/β‑catenin pathway. Searching for an activation model. Cell Signal. 2017;40:30–43.
O’Farrell F, Lobert VH, Sneeggen M, Jain A, Katheder NS, Wenzel EM, et al. Class III phosphatidylinositol-3-OH kinase controls epithelial integrity through endosomal LKB1 regulation. Nat Cell Biol. 2017;19:1412–23.
Sebbagh M, Santoni M-J, Hall B, Borg J-P, Schwartz MA. Regulation of LKB1/STRAD localization and function by E-cadherin. Curr Biol. 2009;19:37–42.
Huo Y, Macara IG. The Par3-like polarity protein Par3L is essential for mammary stem cell maintenance. Nat Cell Biol. 2014;16:529–37.
Gan B, Hu J, Jiang S, Liu Y, Sahin E, Zhuang L, et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature. 2010;468:701–4.
Gurumurthy S, Xie SZ, Alagesan B, Kim J, Yusuf RZ, Saez B, et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature. 2010;468:659–63.
Lai D, Chen Y, Wang F, Jiang L, Wei C. LKB1 controls the pluripotent state of human embryonic stem cells. Cell Reprogram. 2012;14:164–70.
Nakada D, Saunders TL, Morrison SJ. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature. 2010;468:653–8.
Li T, Liu D, Lei X, Jiang Q. Par3L enhances colorectal cancer cell survival by inhibiting Lkb1/AMPK signaling pathway. Biochem Biophys Res Commun. 2017;482:1037–41.
Avtanski DB, Nagalingam A, Bonner MY, Arbiser JL, Saxena NK, Sharma D. Honokiol activates LKB1-miR-34a axis and antagonizes the oncogenic actions of leptin in breast cancer. Oncotarget. 2015;6:29947–62.
Nagalingam A, Arbiser JL, Bonner MY, Saxena NK, Sharma D. Honokiol activates AMP-activated protein kinase in breast cancer cells via an LKB1-dependent pathway and inhibits breast carcinogenesis. Breast Cancer Res. 2012;14:R35.
Seo MS, Kim JH, Kim HJ, Chang KC, Park SW. Honokiol activates the LKB1-AMPK signaling pathway and attenuates the lipid accumulation in hepatocytes. Toxicol Appl Pharmacol. 2015;284:113–24.
Alessi DR, Sakamoto K, Bayascas JR. LKB1-dependent signaling pathways. Annu Rev Biochem. 2006;75:137–63.
Xie Z, Dong Y, Zhang J, Scholz R, Neumann D, Zou M-H. Identification of the serine 307 of LKB1 as a novel phosphorylation site essential for its nucleocytoplasmic transport and endothelial cell angiogenesis. Mol Cell Biol. 2009;29:3582–96.
Zhu H, Moriasi CM, Zhang M, Zhao Y, Zou M-H. Phosphorylation of serine 399 in LKB1 protein short form by protein kinase Cζ is required for its nucleocytoplasmic transport and consequent AMP-activated protein kinase (AMPK) activation. J Biol Chem. 2013;288:16495–505.
Liu L, Siu F-M, Che C-M, Xu A, Wang Y. Akt blocks the tumor suppressor activity of LKB1 by promoting phosphorylation-dependent nuclear retention through 14-3-3 proteins. Am J Transl Res. 2012;4:175–86.
Karuman P, Gozani O, Odze RD, Zhou XC, Zhu H, Shaw R, et al. The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death. Mol Cell. 2001;7:1307–19.
Xie Z, Dong Y, Scholz R, Neumann D, Zou M-H. Phosphorylation of LKB1 at serine 428 by protein kinase C-zeta is required for metformin-enhanced activation of the AMP-activated protein kinase in endothelial cells. Circulation. 2008;117:952–62.
Song P, Xie Z, Wu Y, Xu J, Dong Y, Zou M-H. Protein kinase Czeta-dependent LKB1 serine 428 phosphorylation increases LKB1 nucleus export and apoptosis in endothelial cells. J Biol Chem. 2008;283:12446–55.
Martin SG, St Johnston D. A role for Drosophila LKB1 in anterior-posterior axis formation and epithelial polarity. Nature. 2003;421:379–84.
Shelly M, Cancedda L, Heilshorn S, Sumbre G, Poo M-M. LKB1/STRAD promotes axon initiation during neuronal polarization. Cell. 2007;129:565–77.
Shen Y-AA, Chen Y, Dao DQ, Mayoral SR, Wu L, Meijer D, et al. Phosphorylation of LKB1/Par-4 establishes Schwann cell polarity to initiate and control myelin extent. Nat Commun. 2014;5:4991.
Fogarty S, Hardie DG. C-terminal phosphorylation of LKB1 is not required for regulation of AMP-activated protein kinase, BRSK1, BRSK2, or cell cycle arrest. J Biol Chem. 2009;284:77–84.
Bright NJ, Carling D, Thornton C. Investigating the regulation of brain-specific kinases 1 and 2 by phosphorylation. J Biol Chem. 2008;283:14946–54.
Houde VP, Ritorto MS, Gourlay R, Varghese J, Davies P, Shpiro N, et al. Investigation of LKB1 Ser431 phosphorylation and Cys433 farnesylation using mouse knockin analysis reveals an unexpected role of prenylation in regulating AMPK activity. Biochem J. 2014;458:41–56.
Towler MC, Fogarty S, Hawley SA, Pan DA, Martin DMA, Morrice NA, et al. A novel short splice variant of the tumour suppressor LKB1 is required for spermiogenesis. Biochem J. 2008;416:1–14.
Denison FC, Hiscock NJ, Carling D, Woods A. Characterization of an alternative splice variant of LKB1. J Biol Chem. 2009;284:67–76.
Zheng B, Jeong JH, Asara JM, Yuan Y-Y, Granter SR, Chin L, et al. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell. 2009;33:237–47.
Casimiro MC, Di Sante G, Di Rocco A, Loro E, Pupo C, Pestell TG, et al. Cyclin D1 restrains oncogene-induced autophagy by regulating the AMPK-LKB1 signaling axis. Cancer Res. 2017;77:3391–405.
Bartkova J, Lukas J, Müller H, Lützhøft D, Strauss M, Bartek J. Cyclin D1 protein expression and function in human breast cancer. Int J Cancer. 1994;57:353–61.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.
Inoki K, Zhu T, Guan K-L. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577–90.
Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 2004;6:91–99.
Alexander A, Cai S-L, Kim J, Nanez A, Sahin M, MacLean KH, et al. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci USA. 2010;107:4153–8.
Zheng X, Chi J, Zhi J, Zhang H, Yue D & Zhao J et al. Aurora-A-mediated phosphorylation of LKB1 compromises LKB1/AMPK signaling axis to facilitate NSCLC growth and migration. Oncogene 2017. https://doi.org/10.1038/onc.2017.354.
Tanaka T, Kimura M, Matsunaga K, Fukada D, Mori H, Okano Y. Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res. 1999;59:2041–4.
Boudeau J, Deak M, Lawlor MA, Morrice NA, Alessi DR. Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability. Biochem J. 2003;370:849–57.
Nony P, Gaude H, Rossel M, Fournier L, Rouault J-P, Billaud M. Stability of the Peutz-Jeghers syndrome kinase LKB1 requires its binding to the molecular chaperones Hsp90/Cdc37. Oncogene. 2003;22:9165–75.
Ylikorkala A, Avizienyte E, Tomlinson IP, Tiainen M, Roth S, Loukola A, et al. Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer. Hum Mol Genet. 1999;8:45–51.
Gaude H, Aznar N, Delay A, Bres A, Buchet-Poyau K, Caillat C, et al. Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1. Oncogene. 2012;31:1582–91.
Lee S-W, Li C-F, Jin G, Cai Z, Han F, Chan C-H, et al. Skp2-dependent ubiquitination and activation of LKB1 is essential for cancer cell survival under energy stress. Mol Cell. 2015;57:1022–33.
Yang W-L, Zhang X, Lin H-K. Emerging role of Lys-63 ubiquitination in protein kinase and phosphatase activation and cancer development. Oncogene. 2010;29:4493–503.
Geiss-Friedlander R, Melchior F. Concepts in sumoylation. A decade on. Nat Rev Mol Cell Biol. 2007;8:947–56.
Ritho J, Arold ST, Yeh ETH. A critical SUMO1 modification of LKB1 regulates AMPK activity during energy stress. Cell Rep. 2015;12:734–42.
Konen J, Wilkinson S, Lee B, Fu H, Zhou W, Jiang Y, et al. LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion. Mol Biol Cell. 2016;27:1069–84.
Wilkinson S, Hou Y, Zoine JT, Saltz J, Zhang C, Chen Z, et al. Coordinated cell motility is regulated by a combination of LKB1 farnesylation and kinase activity. Sci Rep. 2017;7:40929.
Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem. 2008;283:27628–35.
Bai B, Man AWC, Yang K, Guo Y, Xu C, Tse H-F, et al. Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1. Oncotarget. 2016;7:39065–81.
Hou X, Xu S, Maitland-Toolan KA, Sato K, Jiang B, Ido Y, et al. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem. 2008;283:20015–26.
Price NL, Gomes AP, Ling AJY, Duarte FV, Martin-Montalvo A, North BJ, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012;15:675–90.
Zu Y, Liu L, Lee MYK, Xu C, Liang Y, Man RY, et al. SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. Circ Res. 2010;106:1384–93.
Tang X, Chen X-F, Wang N-Y, Wang X-M, Liang S-T & Zheng W et al. SIRT2 acts as a cardioprotective deacetylase in pathological cardiac hypertrophy. Circulation; 2017. https://doi.org/10.1161/CIRCULATIONAHA.117.028728.
Barbier-Torres L, Delgado TC, García-Rodríguez JL, Zubiete-Franco I, Fernández-Ramos D, Buqué X, et al. Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer. Oncotarget. 2015;6:2509–23.
MacMicking JD, Nathan C, Hom G, Chartrain N, Fletcher DS, Trumbauer M, et al. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell. 1995;81:641–50.
Liu Z, Dai X, Zhu H, Zhang M, Zou M-H. Lipopolysaccharides promote S-nitrosylation and proteasomal degradation of liver kinase B1 (LKB1) in macrophages in vivo. J Biol Chem. 2015;290:19011–7.
Schaur RJ. Basic aspects of the biochemical reactivity of 4-hydroxynonenal. Mol Asp Med. 2003;24:149–59.
Mali VR, Palaniyandi SS. Regulation and therapeutic strategies of 4-hydroxy-2-nonenal metabolism in heart disease. Free Radic Res. 2014;48:251–63.
Dolinsky VW, Chan AYM, Robillard Frayne I, Light PE, Des Rosiers C, Dyck JRB. Resveratrol prevents the prohypertrophic effects of oxidative stress on LKB1. Circulation. 2009;119:1643–52.
Calamaras TD, Lee C, Lan F, Ido Y, Siwik DA, Colucci WS. Post-translational modification of serine/threonine kinase LKB1 via Adduction of the Reactive Lipid Species 4-Hydroxy-trans-2-nonenal (HNE) at lysine residue 97 directly inhibits kinase activity. J Biol Chem. 2012;287:42400–6.
Calamaras TD, Lee C, Lan F, Ido Y, Siwik DA, Colucci WS. The lipid peroxidation product 4-hydroxy-trans-2-nonenal causes protein synthesis in cardiac myocytes via activated mTORC1-p70S6K-RPS6 signaling. Free Radic Biol Med. 2015;82:137–46.
Walz HA, Shi X, Chouinard M, Bue CA, Navaroli DM, Hayakawa A, et al. Isoform-specific regulation of Akt signaling by the endosomal protein WDFY2. J Biol Chem. 2010;285:14101–8.
Stewart DJ. Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst. 2014;106:djt356.
Chen B, Dodge ME, Tang W, Lu J, Ma Z, Fan C-W, et al. Small molecule–mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol. 2009;5:100–7.
Busch AM, Johnson KC, Stan RV, Sanglikar A, Ahmed Y, Dmitrovsky E, et al. Evidence for tankyrases as antineoplastic targets in lung cancer. BMC Cancer. 2013;13:211.
Huang S-MA, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature. 2009;461:614–20.
Korsse SE, Biermann K, Offerhaus GJA, Wagner A, Dekker E, Mathus-Vliegen EMH, et al. Identification of molecular alterations in gastrointestinal carcinomas and dysplastic hamartomas in Peutz-Jeghers syndrome. Carcinogenesis. 2013;34:1611–9.
Shackelford DB, Abt E, Gerken L, Vasquez DS, Seki A, Leblanc M, et al. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell. 2013;23:143–58.
Ikeda Y, Sato K, Pimentel DR, Sam F, Shaw RJ, Dyck JRB, et al. Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction. J Biol Chem. 2009;284:35839–49.
Zhang W, Wang Q, Wu Y, Moriasi C, Liu Z, Dai X, et al. Endothelial cell-specific liver kinase B1 deletion causes endothelial dysfunction and hypertension in mice in vivo. Circulation. 2014;129:1428–39.
Su JY, Erikson E, Maller JL. Cloning and characterization of a novel serine/threonine protein kinaseexpressed in early Xenopus embryos. J Biol Chem. 1996;271:14430–37.
This work was supported by the German Research Foundation (DFG, SFB1348-A5).
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The authors declare that they have no conflict of interest.
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Kullmann, L., Krahn, M.P. Controlling the master—upstream regulation of the tumor suppressor LKB1. Oncogene 37, 3045–3057 (2018). https://doi.org/10.1038/s41388-018-0145-z
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